The findings from a longitudinal cohort study reported online in the European Heart Journal suggest a simple solution to predicting sudden death in the healthy general population -- a marker that has long eluded cardiologists.

"Few measurements in medicine are as inexpensive and as easy to obtain in large general populations as to measure the heart rate difference between resting and being ready to perform an exercise test," the researchers wrote.

For those who have an exaggerated heart rate response, further cardiovascular tests and tailored primary prevention may be able to reduce ischemic heart disease risk, Dr. Jouven's group said.

Their study included 7,746 male civil servants, ages 42 to 53 at baseline, who were followed for 23 years in the Paris Prospective Study I with a range of testing, including electrocardiograms and an exercise stress test.

In this cohort, Dr. Jouven's group previously found that a low heart rate response to exercise -- an increase of less than 89 beats per minute -- predicted 6.18-fold higher risk of sudden death over the 23-year follow-up period (95 percent confidence interval 2.37 to 16.11).

They also reported in the same New England Journal of Medicine study that sudden death was twice as likely in healthy adults whose heart rate stayed elevated after exercise with a reduction of less than 25 beats per minute.

But while this major physical stress affects the heart rate primarily through the blood-borne catecholamines norepinephrine and epinephrine, mental stress has a different effect, the researchers noted.

It produces a more modest rise in heart rate, which is dependent on simultaneous vagal withdrawal and release of norepinephrine by the nerve endings, rather than systemic release by the adrenal glands.

So, the researchers looked at a surrogate for mental stress in the same cohort: heart rate measured while participants sat on the stationary bike preparing to start the exercise test.

Their mean heart rate jumped 8.9 beats per minute during this period, compared with the at-rest rate.

But the higher the heart rate increase during mild mental stress, the greater the sudden cardiac death risk (P=0.02 for trend).

After adjustment for confounding factors, individuals in the highest tertile for heart rate increase -- more than 12 beats per minute compared with resting -- had 2.09 times greater risk of sudden death (95% CI 1.13 to 3.86) than those in the lowest tertile, who had an increase of less than 4 beats-per-minute.

The group with the most exaggerated heart rate response was also at elevated risk of all-cause mortality during the 23-year follow-up period, though no relationship was seen with non-sudden coronary death.

There was little correlation between heart rate increases before and during exercise. However, mismatch between the two measures appeared to add to risk stratification.

None of the sudden deaths occurred among the group whose heart rate increased the least during mild mental stress, and the most during exercise (relative risk 0.42, 95% CI 0.22 to 0.80).

On the other hand, the largest proportion of these deaths occurred among those whose heart rate increased the most during mild mental stress and the least during exercise (RR 2.33, 95% CI 1.26 to 4.32).

A similar, though lower magnitude, effect was seen for all-cause mortality.

The reason for the association between mental stress and sudden death could be that the autonomic nervous system might act as a "modifier" for the risk of ventricular fibrillation during acute MI, the researchers postulated.

Dr. Jouven likened an MI to hitting the accelerator when the brakes aren't working.

In patients with faster vagal withdrawal in response to mental stress, there is nothing to oppose the body's sympathetic activation in an attempt to counteract reduced blood flow to the heart during MI, he said.

However, the investigators noted that mechanisms besides mental stress were probably at work, too. Postural changes, for example, may have contributed a few beats per minute difference in heart rate, they said.

The authors said it was unclear whether the findings would generalize to women. In addition, they noted that the socioeconomic status, prevalence of smoking, and extent of alcohol use, and other factors in the studied population might differ from the general population.

The study was paid for by national funds given in 1965 to the Groupe de Recherche sur l'Atherosclerose. The researchers reported no conflicts of interest.

Reviewed by Zalman S. Agus, MD Emeritus Professor University of Pennsylvania School of Medicine

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